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HLA-G expression correlates with histological grade but not with prognosis in colorectal carcinoma

cited By 0Trophoblast-specific expression of human leukocyte antigen-G (HLA-G) induces immune tolerance for the developing fetus. Pathological HLA-G expression later in life might contribute to immune escape of various cancers. We studied the still controversial role of HLA-G in colorectal carcinoma (CRC) using the MEM-G/1 antibody and a tissue microarray series of CRC tumors (n = 317). HLA-G expression appeared in 20% of the tumors and showed high intratumoral heterogeneity. HLA-G positivity was associated with better differentiation (p = 0.002) and non-mucinous histology (p = 0.008). However, HLA-G expression alone showed no prognostic value: 5-years disease-specific survival among patients with HLA-G expression was 68.9% (95% CI: 62.7%-75.0%) compared to 74.8% (95% CI: 63.2%-86.3%) among those without expression. These results support a modulatory role of HLA-G in CRC.Peer reviewe

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STRN-ALK rearranged pediatric malignant peritoneal mesothelioma - Functional testing of 527 cancer drugs in patient-derived cancer cells

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene create oncogenic drivers for several cancers, including malignant peritoneal mesothelioma (MPeM). Here, we report genomic and functional precision oncology profiling on a rare case of a 5-year old patient diagnosed with wide-spread and aggressive MPeM, driven by STRN-ALK rearrangement. We established genomically representative patient-derived cancer cells (PDCs) from the tumor sample and performed high-throughput drug sensitivity testing with 527 oncology compounds to identify potent inhibitors. As expected, the PDCs were overall sensitive to the ALK inhibitors, although the eight different inhibitors tested had variable efficacy. We also discovered other effective inhibitors, such as MEK/ERK inhibitors and those targeting pathways downstream of ALK as well as Bcl-xl inhibitors. In contrast, most cytotoxic drugs were not very effective. ALK inhibitors synergized with MEK and PI3K/mTOR inhibitors, highlighting potential combinatorial strategies to enhance drug efficacy and tackle drug resistance. Based on genomic data and associated functional validation, the patient was treated with the ALK inhibitor crizotinib in combination with conventional chemotherapy (cisplatin and gemcitabine). A complete disease remission was reached, lasting now for over 3 years. Our results illustrate a rare pediatric cancer case, and highlight the potential of functional precision oncology to discover pathogenetic drivers, validate dependency on driver signals, compare different inhibitors against each other and potentially enhance targeted treatments by drug combinations. Such real-time implementation of functional precision oncology could pave the way towards safer and more effective personalized cancer therapies for individual pediatric cancer patients with rare tumors.Peer reviewe

Development of the urogenital system is regulated via the 3 ' UTR of GDNF

Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cellline derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3' untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF's effects on progenitors. Moreover, Gdnf(hyper) mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3' UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies.Peer reviewe

GDNF promotes tubulogenesis of GFRα1-expressing MDCK cells by Src-mediated phosphorylation of Met receptor tyrosine kinase

Glial cell line–derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) are multifunctional signaling molecules in embryogenesis. HGF binds to and activates Met receptor tyrosine kinase. The signaling receptor complex for GDNF typically includes both GDNF family receptor α1 (GFRα1) and Ret receptor tyrosine kinase. GDNF can also signal independently of Ret via GFRα1, although the mechanism has remained unclear. We now show that GDNF partially restores ureteric branching morphogenesis in ret-deficient mice with severe renal hypodysplasia. The mechanism of Ret-independent effect of GDNF was therefore studied by the MDCK cell model. In MDCK cells expressing GFRα1 but no Ret, GDNF stimulates branching but not chemotactic migration, whereas both branching and chemotaxis are promoted by GDNF in the cells coexpressing Ret and GFRα1, mimicking HGF/Met responses in wild-type MDCK cells. Indeed, GDNF induces Met phosphorylation in several ret-deficient/GFRα1-positive and GFRα1/Ret-coexpressing cell lines. However, GDNF does not immunoprecipite Met, making a direct interaction between GDNF and Met highly improbable. Met activation is mediated by Src family kinases. The GDNF-induced branching of MDCK cells requires Src activation, whereas the HGF-induced branching does not. Our data show a mechanism for the GDNF-induced branching morphogenesis in non-Ret signaling

Kuinka vasikat oppivat käyttämään juottoautomaattia?

Vasikoiden alkukasvatuksen vaikutuksesta juottoautomaatin käytön oppimiseen on vain vähän tietoa.Tiedetään, että emäänsä imeneet vasikat ovat oppineet paremmin imemään imettäjälehmää kuin tuttiämpäristäjuoneet. Ei ole tutkittua tietoa, kuinka varhainen imemiskokemus vaikuttaa vasikoidenjuottoautomaatin käytön oppimiseen. Emänsä kanssa olleet vasikat eivät ole tottuneet ihmisen käsittelyynniin kuin yksilökarsinaan juotetut vasikat. Tämä voi vaikeuttaa vasikoiden opettamista juottoautomaatinkäyttöön.Jokioisissa Minkiön tutkimusnavetassa tehtiin koe, jossa 41 vasikkaa blokitettiin syntymäjärjestyksessäja arvottiin satunnaisesti koeryhmiin. Neljän ensimmäisen poikimisen jälkeisen päivän ajan vasikatolivat joko emänsä kanssa poikimiskarsinassa (EMO) tai yksilökarsinoissa, joissa saivat ternimaidonjoko avoimesta ämpäristä (ÄMPÄRI) tai tuttiämpäristä (TUTTI). Ternimaitokauden jälkeisenäaamuna n. klo 7.30 (testipäivä 1) yksi vasikka jokaisesta koeryhmästä laitettiin juottoautomaattikarsinaan,jossa oli ennestään kuusi kokenutta vasikkaa (kaksi kustakin käsittelystä, ikä 21±2 pv). Josvasikat eivät olleet kertaakaan onnistuneesti juoneet itse juottoautomaatista, ne ohjattiin automaatilleklo 12.30. Seuraavan kerran vasikat ohjattiin automaatille tarvittaessa klo 17.30 ja seuraavana aamunaklo 7.30 jne.Juottoautomaatin antamista tiedoista laskettiin keskimääräisen juontikerran pituus ja juontimäärätneljän ensimmäisen päivän aikana. Juottoautomaattia videoitiin 48 ensimmäistä tuntia. Videoista rekisteröitiinvasikoiden viettämä aika juottoautomaatin ovensuulla, kun automaatti oli tyhjä tai siellä olitoinen vasikka/hoitaja (suhteessa ovella vietettyyn kokonaisaikaan). Lisäksi laskettiin opetuskertojenmäärät. Kolme vanhinta vasikkaa (yksi kustakin käsittelystä) siirrettiin pois karsinasta testipäivänä 4.Ryhmien väliset erot testattiin sekamallilla.Ensimmäisenä päivänä TUTTI -vasikat olivat juottoautomaatin ovensuussa enemmän kuin EMOtaiÄMPÄRI- vasikat silloin, kun hoitaja oli automaatissa opettamassa toisia vasikoita (16 ± 7 % ja 1 ±0.5 % tai 5 ± 3 %, p=0.009 ja p=0.05.). Toisena päivänä suurempi osuus EMO- vasikoista tarvitsiopetusta juottoautomaatin käyttöön kuin TUTTI- ja ÄMPÄRI – vasikoista (77 % ja 36 % tai 43 %,p=0.07). TUTTI -vasikat joivat kahtena ensimmäisenä päivänä nopeammin kuin muiden ryhmien vasikat.Maidonkulutuksessa ei havaittu eroja käsittelyjen välillä.Tuttiämpäristä juoneet vasikat käyttivät juottoautomaatin tuttia tehokkaammin kuin avoämpäristäjuoneet tai emosta imeneet vasikat. Maidon juominen imemällä oli yksilökarsinoiden vasikoille kentiespalkitsevampi kokemus kuin juominen avoämpäristä ja vasikat leimautuivat vahvemmin ihmiseen.Vieroitus emästä ja vähäinen ihmiskontakti lienee vaikeuttanut emon alla pidettyjen vasikoiden oppimista

Simple 3D culture of dissociated kidney mesenchyme mimics nephron progenitor niche and facilitates nephrogenesis Wnt-independently

Kidney mesenchyme (KM) and nephron progenitors (NPs) depend on WNT activity, and their culture in vitro requires extensive repertoire of recombinant proteins and chemicals. Here we established a robust, simple culture of mouse KM using a combination of 3D Matrigel and growth media supplemented with Fibroblast Growth Factor 2 (FGF2) and Src inhibitor PP2. This allows dissociated KM to spontaneously self-organize into spheres. To reassess the requirement of WNT activity in KM self-organization and NPs maintenance, cells were cultured with short pulse of high-dose GSK3 beta inhibitor BIO, on a constant low-dose or without BIO. Robust proliferation at 48 hours and differentiation at 1 week were observed in cultures with high BIO pulse. Importantly, dissociated KM cultured without BIO, similarly to that exposed to constant low dose of BIO, maintained NPs up to one week and spontaneously differentiated into nephron tubules at 3 weeks of culture. Our results show that KM is maintained and induced to differentiate in a simple culture system. They also imply that GSK3 beta/WNT-independent pathways contribute to the maintenance and induction of mouse KM. The robust and easy 3D culture enables further characterization of NPs, and may facilitate disease modeling when applied to human cells.Peer reviewe

Development of the urogenital system is regulated via the 3 ' UTR of GDNF

Mechanisms controlling ureter lenght and the position of the kidney are poorly understood. Glial cellline derived neurotrophic factor (GDNF) induced RET signaling is critical for ureteric bud outgrowth, but the function of endogenous GDNF in further renal differentiation and urogenital system development remains discursive. Here we analyzed mice where 3' untranslated region (UTR) of GDNF is replaced with sequence less responsive to microRNA-mediated regulation, leading to increased GDNF expression specifically in cells naturally transcribing Gdnf. We demonstrate that increased Gdnf leads to short ureters in kidneys located in an abnormally caudal position thus resembling human pelvic kidneys. High GDNF levels expand collecting ductal progenitors at the expense of ureteric trunk elongation and result in expanded tip and short trunk phenotype due to changes in cell cycle length and progenitor motility. MEK-inhibition rescues these defects suggesting that MAPK-activity mediates GDNF's effects on progenitors. Moreover, Gdnf(hyper) mice are infertile likely due to effects of excess GDNF on distal ureter remodeling. Our findings suggest that dysregulation of GDNF levels, for example via alterations in 3' UTR, may account for a subset of congenital anomalies of the kidney and urinary tract (CAKUT) and/or congenital infertility cases in humans and pave way to future studies